Metabolic syndrome, obesity, diabetes, and theier implications

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1 Metabolic syndrome, obesity, diabetes, and theier implications Institute of Medical Biochemistry and Laboratory Diagnostics &1 st Department of Medicine

2 Diabetes mellitus type 2 (T2DM) - obesity Clinical level: obesity T2DM vascular complications tumours Alzheimer disease Cellular/biochemical levels: glucose carbonyl stress/non-enzymatic glycation lipides (FFA) oxidation stress

3 Diabetes mellitus type 2 (T2DM) - obesity Clinical level: obesity T2DM vascular complications tumours Alzheimer disease CHRONIC SUBCLINICAL (micro)inflammation Cellular/biochemical levels: glucose carbonyl stress/non-enzymatic glycation lipides (FFA) oxidation stress

4 79 % of T2DM patients are overweight or obese 63 % of T2DM patients have arterial hypertension 70 % of T2DM patients have dyslipidemia Libby et al. Circulation 2002;106(22): Jacobs et al. Diabetes Res Clin Pract. 2005;70(3):

5 Metabolic syndrome described by Reaven in 1988 T2DM (insulin resistance hyperglycemia + hyperinsulinaemia) dyslipidemia ( HDL, (ox)ldl, TAG) hypertension visceral obesity

6

7 Adipokines: Pro-inflammatory: TNF-α, TGF β, leptin, resistin Anti-inflammatory: adiponectin Ravussin et al, 2002

8 Myokines: anti-inflammatory, pro-regenerative effects

9 BMI and mortality in elderly Save your muscle!!! Winter JE. Am J Clin Nutr 2014, 99:

10 Diabetes mellitus Increasing incidence (type 2 DM) life expectancy life quality long-term complications

11 Long term complication of diabetes mellitus

12 T2DM pathogenesis: Death octet (DeFronzo, 2009) described by Reaven in 1988

13 Metabolic syndrome/t2dm/obesity insulin resistance hyperinsulinaemia growth factor proliferation of vessel wall, chronic inflammation, tumour cells fixation of FA in fat tissue insulin inhibits fat tissue reduction

14 Metabolic syndrome consequence enos activity + NO degradation + angiotensin II endothelial dysfunction - vasoconstriction insulin resistance insulin/insulin-1 growth factor (IGF-1) vascular smooth muscle cell proliferation/vascular and cardiac fibroblast migration and proliferation vascular wall (myocard) hypertrophy insulin/igf-1 risk of tumour growth plasminogen activator inhibitor-1 procoagulation status

15 Metabolic syndrome consequence abnormal accumulation of visceral fat inflammatory cytokines chronic inflammation status All together tissue/organ ischemia cardiovascular/cerebrovascular disease risk

16 Toxic effect of hyperglycemia - mechanism 1. Polyol pathway 2. Advanced Glycation End-products formation 3. Protein kinase C pathway 4. Hexosamine pathway

17 Effect of superoxide production

18 Polyol pathway

19 Polyol pathway Consumption of reduced NADPH glutathione regeneration intracellular oxidative stress

20 Advanced Glycation End-products (AGEs) - formation created by M. Kalousová

21 Advanced Glycation End-products (AGEs) - formation Glucose AGEs formation importance: development of long-time complications laboratory marker of diabetes compensation (HbA1)

22 Advanced Glycation End-products - action

23 Advanced Glycation End-products - action Endothelial cell: intracellular generation of AGEs precursors (e.g. glyoxal) intracellular action intracellular proteins glycation affected gene transcription extracellular transport matrix proteins glycation affected cell-matrix interaction extracellular transport AGEs formation AGE-RAGE interaction nuclear NF- B pro-inflammatory cytokines and growth factors

24 Protein kinase C pathway

25 Protein kinase C pathway Vascular/blood effect: vasoconstriction, occlusion, pro-coagulation Global effect: inflammation, protein/dna damage INFLAMMATION ISCHEMIA

26 Hexosamine pathway

27 Hexosamine pathway GFAT: glutamine:fructose-6-p amidotransferase UDP-N-acetyl glucoseamine binding to serine + threonine residues modification of transcription factors overexpession of pro-inflammatory/pro-coagulation factors ISCHEMIA

28 Hyperglycaemia induces superoxide production in mitochondria Excess of NADH+H + /FADH 2 Block of complex III superoxide formation

29 Effect of superoxide production Superoxide production activation of nuclear PARP /poly(adp- ribose) polymerase/ inhibition of GAPDH accumulatin of glycolysis metabolites activation of damaging pathways

30 PARP inhibits GAPDH - mechanism

31 PARP inhibits GAPDH Mechanism: depletion of NAD + (cofactor of GAPDH) poly(adp- ribosy)lation Consequence: inhibition of glycolysis, resulting excess of glycolysis metabolites activation of damaging pathways endothelial dysfunction, iflammation, ISCHEMIA

32 PARP inhibits GAPDH - consequence

33 Carbonyl stress (methyl)glyoxal generation glucose (methyl)glyoxal generation (MG)

34 T2DM - therapy Change of lifestyle body weight reduction Pharmakotherapy: metformin (biquanides) 1st line therapy potential anticancer effects gliflozins - inhibitors of SGLT-2 (sodium-glucose co-transporter type 2) cardiovascular protection in T2DM patiens

35 Metabolic syndrome/t2dm - further therapy inhibition of renin-angiotensin-aldosterone system - ACE inhibitors - AT1 receptor blockers lowering of blood pressure antiproliferative effect (fibroblasts, VSMCc, cardiomyocytes) statins (HMG-CoA reductase inhibitors) lowering of hypercholesterolemia/improvement of dyslipidemia antiproliferative effect (fibroblasts, VSMCc, cardiomyocytes)

36 Take home message/vezměte si (domů Hyperglykémie (dlouhodobá) je nebezpečná Hypoglykémie zabíjí Dlouhodobá hyperglykémie vede k chronickému (mikro)zánětu Chronický (mikro)zánět poškozuje cévy Ve vyšším věku je lepší mít mírnou nadváhu Sval si zaslouží ochranu

37 References: Brownlee M /Diabetes 54, 2005/ Kanwar YS et al /Exp Biol Med 233, 2008/ Porter KE, Turner NA /Pharmacol Ther 123, 2009/ Duan SZ et al /Circ Res 102, 2008/ Pacher P, Szabo C /Antioxid Redox Signal 7, 2005/ Turk Z /Physiol Res 59, 2010/ Svačina Š /výběr z prezentací/

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